A currently existing agent for the clinical imaging of pulmonary circulation is 99mTc-labelled albumin macroaggregates. This agent is used for the diagnosis of physical defects of the circulation due to pulmonary embolus. This agent is larger than small pulmonary vessels. Accordingly, further to being injected in an animal, this agent is trapped by these small pulmonary vessels, which enables external detection.
Important limitations of albumin macroaggregates include the inability to image the small pulmonary circulation beyond the point of obstruction. This limits the sensitivity of this substance to detect small vascular defects. Also, there are potential infectious risks since albumin macroaggregates are derived from human albumin. Additionally, albumin macroaggregates are unable to detect functional (biological) defects of the pulmonary circulation since their retention is uniquely dependent on physical characteristics of the vessels.
In addition, many other pulmonary diseases are difficult to diagnose. For example, pulmonary arterial hypertension (PAH) is a disorder characterized by endothelial dysfunction with intimal as well as vascular smooth muscle proliferation leading to gradual obliteration of pulmonary arterioles [36]. Screening for PAH is performed by transthoracic Doppler echocardiography with estimation of the pulmonary artery systolic pressure using the tricuspid valve regurgitant jet. Although this approach correlates with hemodynamically measured pulmonary pressure, it does not provide direct information on the biology of the pulmonary circulation and may miss the early presence of pulmonary vascular disease. The recent availability of oral therapies for PAH such as endothelin receptor antagonists and phophodiesterase inhibitors advocate for earlier diagnosis of this condition and treatment of subjects in functional class II. There is therefore imperious necessity for novel diagnostic approaches of this appalling condition that could provide earlier and more precise diagnosis.
There exist compounds that have an affinity for particular organs, such as for example adrenomedullin (AM). AM is a 52-amino-acid multifunctional regulatory peptide highly expressed in endothelial cells and widely distributed in various tissues [1,2]. The structure of AM is well conserved across species, with only six substitutions and two deletions in the rat [rAM(1-50)] compared with the human [hAM(1-52)] [3]. AM possesses structural homology with CGRP (calcitonin gene-related peptide), making it a member of the calcitonin/CGRP/amylin family (CT/CGRP/AMY peptide family).
The biological activities of AM are mediated by receptors composed of two essential structural components: a seven-transmembrane protein, the calcitonin receptor-like receptor (CRLR), and a single transmembrane domain termed RAMP (receptor-activity-modifying protein) [4,5]. The association of CRLR/RAMP1 represents the CGRP1 receptor and is not specific to AM. At the opposite, a specific AM receptor comes from the coupling of CRLR/RAMP2 or CLRL/RAMP3 [6]. This specific AM receptor can be blocked by the C-terminal AM fragment [hAM(22-52)][7].
A biological action of AM is a potent hypotensive effect. The systemic hypotensive action of AM can however be reduced and sometimes abolished after intravenous compared with intra-arterial infusion [8], suggesting that the lungs have a potential to clear circulating AM and modulate its circulating levels. Many studies have confirmed that AM is cleared by the pulmonary circulation [9-12]. However, the relative contribution of the lungs to AM clearance in comparison with other organs has not been systematically evaluated and, more specifically, single-pass pulmonary clearance of AM has not been quantified in vivo. In addition, the exact region of the AM peptide that is responsible for the hypotensive effects is currently unknown.
Against this background, there exists a need in the industry to provide novel compounds having an affinity for the lungs, the kidneys and other organs, and more specifically to provide such compounds suitable for use in therapy and imaging.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.